The staggering global toll taken by infectious diseases calls for vastly more effective monitoring, as well as new preventative and therapeutic measures. To address critical gaps in our knowledge about the basic biology of key pathogens and their interactions with their hosts and insect vectors, we will create a Genomic Center for Infectious Diseases (GCID). Our team combines an extensive track record of developing and applying groundbreaking laboratory and analytical methods with experience managing large and complex projects to produce resources for the infectious disease research community. We will use genomic methods to define the extent of variation among organisms, as well as among microbial communities. Our viral research will focus on the NIAID Category A priority pathogens Lassa and Dengue viruses, and the Category B priority pathogen West Nile virus, as well on surveillance for fever-causing viruses in tropical developing countries. Bacterial studies will focus on the Category C priority pathogens M. tuberculosis and Carbapenem-resistant Enterobacteriaceae, an emerging cause of nocosomial infections associated with high mortality, as well as the costly Uropathogenic E. coli. Fungal research will focus on major pathogens with significant clinical impact, C. neoformans and C. albicans, as well as strains causing recent fungal outbreaks, including C. gattii and Fusarium spp. We will also study both the malaria-causing parasite P. falciparum and its mosquito vector, A. gambiae. In studying these particular high-priority pathogens as model systems, we will produce, and train community members to use, new methods of wide utility. We will sequence natural isolates as well as laboratory-derived mutants, and associate sequence differences with phenotypes to help interpret the functional consequences of this variation with respect to virulence, transmission and drug sensitivity. Working at several levels, from populations to whole organisms, and animal models to single cells, we will reveal the long term (evolutionary) responses to pathogen and host interactions and exposure to drugs or insecticides as well as the immediate (transcriptional) responses of host and pathogens to infection. These responses define potential new opportunities for interventions to disrupt the cycle of infection and transmission. In bringing together outstanding investigators in infectious disease with cutting edge laboratory and analytical methods and experienced leaders in genomics, we will generate the information needed to create new tools to track, diagnose, treat and prevent infectious diseases.